Our ultimate goal is to attempt to unravel the multifaceted process of aging and reduce it to a finite number of well-defined molecular processes that likely interact with environmental factors. This should give us insight into the basic mechanisms of aging and provide new possibilities for early diagnosis and medical intervention. We plan to closely couple basic molecular studies on aging to physiological endpoints. Indeed, to optimally apply the recent windfall of new advanced techniques in molecular biology to the benefit of gerontology, it is of the utmost importance to bring together basic research and functional correlations. As a model for this we have adopted the hypothesis that DNA damage, mutation and dysfunction contribute to physiological decline and disease during aging. Using the latest technology, we will study (1) somatic mutation frequency, (2) relative DNA repair proficiency, (3) gene expression regulation, and (4) mitochondrial energetics. This will allow us to define a role, if any, of DNA changes in specific aging problems. The added value of the program is that we will be able to relate the different data sets to one another. Finally, the program project could serve as a model for future studies on molecular parameters in conjunction with functional outcomes.